Transcript Research Priorities in Venous Disease Mark H. Meissner, MD Professor of Surgery University of Washington School of Medicine Seattle, WA.

Research Priorities in Venous
Disease
Mark H. Meissner, MD
Professor of Surgery
University of Washington School of Medicine
Seattle, WA
Research Priorities in Venous Disease
27 Original Questions

What is the role of prophylactic IVC filters – Is PE/death
reduced compared to other methods of VTE prophylaxis
or duplex surveillance or both?
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What are the outcomes of treated isolated calf vein
thrombosis compared with the natural history of
untreated calf DVT?
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Develop best practices for management of chronic
venous ulceration
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What is the comparative effectiveness of compression
therapy versus ablation in preventing the progression of
chronic venous disease?

What is the role of Chronic Cerebrospinal Venous
Insufficiency (CCSVI) in Multiple Sclerosis?
What is the role of prophylactic IVC
filters – Is PE/death reduced compared
to other methods of VTE prophylaxis
or duplex surveillance or both?
Trends in IVC Filtration
Stein PD, Am J Med 2001
Retrievable
Filters
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National Hospital Discharge Survey 1979 – 2006
Increased filter use from 1979 (17,000) to 2006 (803,000)
3X increase in prophylactic filter use after 2003
 2001 – 0.02% of discharge sample
 2006 – 0.06% of discharge sample
Venous Thromboembolism & Trauma
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Thromboembolic risk in seriously injured patients
 Distal DVT – 58%
 Proximal DVT – 18%
3rd leading case of death in patients surviving 24 hrs
22% with ongoing bleeding or high risk of bleeding
3X increased risk with delayed prophylaxis (96 vs 48 hrs)
 No benefit for LDUFH vs placebo (OR 0.96, 0.36 – 2.96)
 No benefit for SCDs vs placebo (OR 0.77, 0.26 – 2.23)
DVT Prophylaxis in Trauma
Geerts et al, N Engl J Med 1996
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344 patients followed with venography
 Heparin 5000u bid - 136 patients
 Enoxaparin 30 mg bid - 129 patients
Heparin
Enoxaparin
p
DVT
Proximal DVT
44%
15%
31%
6%
0.014
0.012
Major Bleeding
0.6%
2.9%
0.12
ACCP Guidelines for Trauma
Geerts et al, Chest 2008
Guideline
GRADE
Recommendation
For major trauma patients, in the absence of a major
contraindication, we recommend LMWH thromboprophylaxis
starting as soon as it is considered safe
1A
If LMWH is contraindicated due to active bleeding or high risk for
clinically important bleeding, we recommend mechanical
thromboprophylaxis
1B
We recommend against routine DUS screening .. But, we do
recommend DUS screening in patients at high risk for VTE (i.e.
SCI) and who have received suboptimal or no prophylaxis
1C
We recommend against the use of an IVC filter for
thromboprophylaxis
1C
EAST Guidelines
Rogers FB et al, J Trauma 2002
Guideline
Level of Evidence
Little evidence exists to support LDUFH as a sole agent for
prophylaxis
II
No benefit of the use of SCDs over no prophylaxis. In the
subset of head injured patients, SCDs may have some benefit.
III
LMWH can be used with the following injury patterns 1)
Pelvic fractures, 2) Complex lower extremity fractures, 3)
Spinal cord injury
II
Insertion of a prophylactic IVC filter should be considered in
very high risk trauma patients who cannot receive
anticoagulation
III
Serial duplex ultrasound imaging of asymptomatic patients
may be cost effective and decrease the incidence of PE
III
IVC Filters & Trauma
Rajesekhar et al, J Thromb Thrombolysis 2011
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Metanalysis of 7 cohort studies (No randomized trials)
 1900 high-risk trauma patients
 Permanent Greenfield filter in 6/7 studies
Lower PE risk with IVC filter (OR 0.21, 0.009 – 0.49)
Trend towards increased DVT (OR 1.6, 0.76 – 3.37)
Limitations
 Inconsistent use of pharmacologic prophylaxis
 3/6 studies prior to 1996
Insufficient evidence to support prophylactic filters in trauma
Cost Effectiveness of VTE Prophylaxis
Chiasson TC, Plos 2011
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Severely injured patient cohort (N = 10115)
 2 wk contraindication to anticoagulants
 ISS > 12
 Head / neck or abdomen / pelvis AIS ≥ 3
Markov modeling of 3 prophylactic strategies
Outcome
SCD only
SCD + Duplex
Prophylactic VCF
DVT %
14.9
15.0
25.7
PE %
2.9
1.5
0.3
Mortality %
24.5
24.4
24.5
Cost ($ Can)
55, 831
55, 334
57, 377
Duplex surveillance strategy dominant
VCF filter costs
 11 additional DVTS per PE prevented
 $204,000 per PE prevented
Is Pharmacologic Prophylaxis Contraindicated?
Koehler et al, J Trauma 2011
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669 patients with acute intracranial hemorrhage (ICH)
Enoxaparin 30 mg q 12 hours
 Early (0 – 72 hrs) prophylaxis - 268 (40.1%)
 Late ( > 72 hrs) prophylaxis - 401 (59.9%)
No deaths from ICH pregression
1 death (late prophylaxis) from PE
Early Prophylaxis
Late Prophylaxis
p
ICH Progression
1.46%
1.54%
0.9
Pulmonary Embolism
1.5%
2.2%
0.49
Proximal DVT
1.5%
3.5%
0.1
Distal DVT
3.7%
6.7%
0.09
“ Early prophylaxis appears safe for patients with TBI”
FDA Warning
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices
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Concern regarding 921 adverse event reports since 2005
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Device migration – 328
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Embolization – 146
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IVC perforation – 70
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Fracture – 56
Planned risk / benefit decision analysis
“FDA recommends that implanting physicians and
clinicians responsible for the ongoing care of patients
with retrievable IVC filters consider removing the filter
as soon as protection from PE is no longer needed”
CER Research – Registry Approaches
www.venousregistry.org
The trusted venous resource
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American Venous Forum Registries
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Venous stent module
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Varicose vein module (launched 11/10)
“Real world” comparison of
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Technical outcomes (patency, closure rates)
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Clinical outcomes (VCSS)
Conclusions
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Anticoagulation remains gold standard
Paucity of quality evidence to support filters
 Standard indications - 2C
 Prophylaxis - 1A Against
Filter choice dependent on design
 Single stage filtration
 Deep conical design
 Short radius hooks
Permanent filters for permanent indication
Consider temporary filters
 Age < 65
 No malignancy
What are the outcomes of treated isolated
calf vein thrombosis compared with the
natural history of untreated calf DVT?
Fibrinogen Uptake and Post-Operative DVT
Why we are talking about this today
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“Minimal” calf vein thrombosis
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Frequently
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Small, non-occlusive
Asymptomatic
Early resolution
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Diagnosed by 125I-labeled fibrinogen uptake
Sensitive to small (or non-existent) tibial vein thrombi
Doouss TW (1976) - 84% resolved by discharge
Kakkar et al (1969) - 35% resolved within 72 hrs
Low incidence of propagation
Low incidence of symptomatic pulmonary embolism
Don’t treat “below knee” DVT
Venous Duplex Ultrasonography
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Most widely used diagnostic test for DVT
Sensitivity and specificity > 90% for symptomatic proximal DVT
The relevance (and even the need to look for) of ultrasound
identified calf vein thrombosis remains controversial
ACCP Consensus Guidelines
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2001 - “symptomatic isolated calf vein thrombosis should be
treated with anticoagulation for 6 - 12 weeks. (Grade 1A) If for
any reason anticoagulation is not administered, we recommend
that serial non-invasive studies of the lower extremity should
be performed…”
2004 - ???
2008 - “For patients with a first isolated distal DVT that is
unprovoked,
we suggest that 3 months of anticoagulation
is sufficient rather than indefinite therapy” (Grade 2B)
Is There Data to Guide Management?
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Natural History Studies
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Observational (cohort)
studies
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Randomized trials
Natural History of DVT
Meissner et al, J Vasc Surg 1996
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499 patients with DVT in 576 limbs
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452 (91%) with proximal thrombosis
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47 (9%) with isolated CVT
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Duplex f/u at 1 day, 1 month, q 3 months X 1yr, q yr
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Median follow-up 111 days
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Outcomes
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Proximal propagation in 6 (16%) of isolated CVT
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11% concurrent PE
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PTS (1 yr) – 54% proximal versus 23% isolated CVT
D-Dimer > 1000 ug/ml highly predictive of propagation
Natural History Based Mathematical Models
Modified from Raskob, 1996
Isolated Calf Vein Thrombosis
20% Propagation
20 - 50% Recurrent
VTE
5-10% Symptomatic
PE
No Propagation
1% Fatal PE
10% Fatal PE
?? Embolic
Risk
Cohort Studies – The CALTHRO Study
Palareti G, Thromb Haemost 2010
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431 pts with (–) proximal U/S and…
Symptomatic
(N = 3470)
 High PTP or…
 Low PTP and (+) D-Dimer
Proximal Compression U/S
Pre-Test Probability (Well’s)
Complete U/S results withheld
D-Dimer
 (+) CVT – 65 (15%)
Low PTP
Positive U/S
Negative U/S
 (-) CVT – 359 (18%)
(n = 370)
Negative DDimer
Proximal DVT/PE at 3 mo (p = .003)
Low PTP (n = 1212)
High PTP
Negative U/S
 Untreated CVT – 5 / 65 (7.8%)
Negative U/S
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No CVT – 3 / 359 (0.8%)
Limitations
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(n = 327)
Positive DDimer
(n = 1561)
Enrolled in study
(n = 431)
Non consecutive enrollment
Outpatients only
Complete U/S including calf veins
Physician / patient blinded to results
Randomized Clinical Trials
Lagerstedt al, Lancet 1985
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Randomized study of 51 patients with CVT
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Heparin X 5 Days (N=28)
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Heparin X 5 Days
Warfarin X 3 mo (N=23)
Warfarin group
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No recurrence
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9% (N=2) major hemorrhage
Heparin only group
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29% recurrence
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18% proximal propagation
Randomized Trials – ICMVT
Schwarz et al, J Vasc Surg 2010
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109 consecutive pts with muscular calf vein thrombosis
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89% outpatients
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69 (63%) soleal, 40 (37%) gastrocnemial thrombi
Randomized to
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Therapeutic LMWH X 10 days + compression stockings
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Compression stockings
Progression to deep axial veins at 3 months (p = ns)
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LMWH – 3 / 54 (5.6%) at 20 and 28 days
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Compression – 3 / 53 (5.7%) at 8 and 31 days
No proximal DVT, symptomatic PE, or death
Isolated Calf Vein Thrombosis
What is the evidence to guide anticoagulation?
Data
Anticoagualtio
n?
Grade of
Evidence
Natural History
Studies
20% propagation, 10%
concurrent PE, 23% PTS
Favors
C
Mathematical
Models
5 – 10 % Recurrent VTE
2 % Fatal PE
Favors
C
Cohort Studies
7.8% Recurrent VTE
Favors
C
RCTs
CVT – 29% Recurrent VTE
CVT – Favors
MCVT – 5.7% Recurrent
MCVT - No
VTE
But…
High Quality (Grade A) Data Is Lacking
B
The evidence supports anticoagulating at least some isolated
CVT in at least some patients at least some of the time
But….
All isolated CVT are not equal
Irreversible Risk
Factors
Age
Malignancy
Hypercoagulability
Transient Risk
Factors
Surgery
Trauma
Estrogen
Idiopathic DVT
Immobile
Isolated Calf Vein
Thrombosis
Outpatient
Ambulatory
Inpatient
Axial CVT
Muscular CVT
Summary of the Evidence
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Natural history differs from proximal DVT
 Fewer risk factors
 Lower prevalence of malignancy
 More rapid recanalization
Complications fewer but not trivial
 20% risk of propagation
 Symptomatic PE in 10% at presentation
 Recurrent VTE in 5-10%, fatal PE in 1% untreated
 One quarter remain symptomatic at 1 year
Anticoagulation is appropriate in at least some patients and
those not anticoagulated should be followed with serial U/S
What we don’t know is who can be safely followed
At present, clinical judgment is critical
Pending Randomized Trials
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CACTUS University Hospital, Montpellier, France
600 patients with isolated CVT
 Nadroparin X 6 weeks vs placebo
 1º Outcome – 6 week U/S extension to proximal veins
DiVeTAS University of Washington, Seattle, WA
 600 patients (6 centers) with isolated CVT
 Warfarin X 3 months vs duplex U/S surveillance
 1º outcome – Propagation, PE, bleeding & mortality
(composite)
 2º outcomes
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Identification of high risk groups
Clinical & anatomic factors
Biomarkers
Long term outcome – PTS & quality of life
Cost
Develop best practices for the
management of chronic venous
ulceration
Venous Leg Ulceration
The Public Health Impact
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1 – 1.5% Prevalence of active ulcers in Western populations
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100% recurrence without effective treatment
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Limitations comparable to other chronic diseases
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10% unable to work
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2,000,000 lost work days per year
90% require medical treatment
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1% of healthcare costs of Western European countries
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Mean cost of € 9569 ($13, 130) / patient / year (Germany)
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Annual costs of £ 300 to 600 million in the UK
The Landscape of VLU guidelines
O’Donnell TF, J Vasc Surg 2011
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Systematic survey of published VLU guidelines (N = 14)
Guideline
Inclusion
Strongly Recommended
Recommended
Clinical Exam
14 (100%)
3 (23%)
4 (31%)
Doppler ABI
14 (100)
6 (46)
4 (31)
Venous Duplex
9 (64)
4 (44)
2 (22)
Cleanse Wound
13 (93)
3 (25)
4 (33)
Wound
Debride Wound
12 (86)
4 (36)
3 (27)
Care
Dressings
14 (100)
10 (77)
2 (15)
Compression
14 (100)
9 (75)
3 (23)
Adjunctive
Skin Graft
10 (71)
5 (56)
4 (44)
Treatment
Pentoxyfylline
11 (79)
7 (64)
2 (18)
Prevention of
BK Stockings
13 (93)
7 (58)
2 (18)
Recurrence
Superficial Surgery
11 (79)
8 (73)
1 (9)
Diagnosis
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Poorly coordinated
Poorly adopted
Many areas not addressed (e.g perforator surgery)
The 6th Pacific Vascular Symposium
Henke P, J Vasc Surg 2011
50% Reduction in VLU within 10 yrs
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Monthly conference calls initiated in December 2010
Initial priorities
 Establish current ulcer prevalence in the U.S
 Venous guidelines (Bill Marston & Tom O’Donnell)
Key wound care societies (WHS & AAWC) engaged
Planned systematic reviews & meta-analyses
Obvious need for SVS involvement & support
What is the comparative effectiveness
of compression therapy versus
ablation in preventing the progression
of chronic venous disease?
The Utility of Venous Interventions
The REACTIV Trial (Ratcliffe , Br J Surg 2006)
Conservative
Surgery
Mean Difference
Mean NHS Cost
£344.53
£733.10
£388.57
AUC SF-6D
1.42
1.50
0.083
ICER *
£4682
* Incremental cost effectiveness ratio
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246 patients extensive vv and saphenous reflux randomized to
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Conservative measures (n = 122)
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Saphenous stripping / phlebectomy (n = 124)
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24 mo cost effectiveness of £4682 per QALY gained
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Below NHS threshold of £20,000 per QALY
Venous Disease – Comparative Effectiveness
Gohel, BJS 2010
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Markov model based on 2 metanalyses, 1 RCT
Odds ratio of GSV occlusion (Stripping versus…)
 Laser ablation – 0.97
 Radiofrequency ablation – 0.84
 U/S guided foam sclerotherapy – 3.01
0.1 QALY / yr gained with intervention
Treatment
5 Yr Costs
(£)
Incremental QALY
Gained
ICER
(£ / QALY)
Conservative
0
-
-
UGFS
429
0.314
1360
Laser
1031
0.104
5799
Radiofrequency
1110
0.005
17,360
Stripping/phleb
1242
0.007
19,012
However, substantial uncertainty in estimates
Robust comparative effectiveness data is needed
Intervention improves QALYs, but…CVD is a chronic disease and is
there any evidence that intervention is effective in preventing
progression?
•What is the number need to treat to prevent 1 ulcer?
•What is the cost of preventing 1 ulcer?
•What is the comparative effectiveness of different treatments?
Primary Venous Disease
The Bonn Vein Study, J Vasc Surg 2008
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Cross sectional sample of 3072 subjects
2% per year progression to CVI (C3 – C6)
Risk factors for progression
 Age
 Arterial hypertension
 Obesity
CVD Progression – The Problems
Pacific Vascular Symposium 6, J Vasc Surg 2010
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Most patients with CVD do not progress to C4 – 6
Advanced CVD is a multifactorial disease
 Age
 Obesity
 Gender
 Hypertension
 Occupation
 HFE polymorphisms
 AT deficiency
Number needed to prevent 1 ulcer (NNT) is unknown
Could a CER Analysis Be Done?
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Theoretical randomized trial to reduce
progression from C1-2 to C3-6 by 50%
 Observation only
 Superficial venous intervention
Assumptions
 2% per year progression
 5 year reduction in progression from 10% to
5%
 Alpha error = 0.5, 80% power
 20% loss to follow-up
440 patients per group
1056 patients required
5 year claudication CER study cost $12 million
Venous Interventions
Comparative Effectiveness
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The United States health care quandry
 Regulatory environment favors innovation over effectiveness
 Increases in technology costs are unsustainable
Cost-consequence analysis and comparative effectiveness are
increasingly important
What we know
 Venous interventions improve quality of life
 Venous interventions are cost effective at standard
willingness to pay thresholds
 Some effective interventions are far cheaper than others
 Device costs based on “what the market will bear” probably
can’t continue
What we don’t know
 Cost-effectiveness of interventions to prevent progression
 Comparative effectiveness of different interventions
What is the leading cause of
disability in young & middle aged
people in the developed world?
Multiple Sclerosis
Koch-Henriksen, Lancet Neurology 2010
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Demyelinating immune mediated CNS disease
Leading cause of disability in young / middle aged patients
Epidemiology
 Peak incidence at age 30
 Peak prevalence at age 50
 North American incidence of 100 – 200/100,000
 Increasing incidence, particularly in females
Complex etiology
 Genetic factors
 Environmental factors
 Socioeconomic factors
But …. Is MS a primary vascular disorder
Chronic Cerebrospinal Venous Insufficiency (CCSVI)
Zamboni, Phlebology 2010
Leukocyte Activation, Adhesion,
Migration
Venous
Reflux
RBC Extravasation
Protein Extravasation
Decreased
Shear
IJV / Azygous Stenosis
in 56% - 100% of MS
patients
Inflammation
Endothelial Activation
Perivenous Iron Deposition
Fibrin Cuffing
Chronic Cerebrospinal Venous Insufficiency
Zamboni, J Neurol Neurosurg Psychiatry 2009
MS
(n = 65)
Controls
(n = 235)
Reflux in IJVs or vertebral veins (VVs) > 0.88 s
71%
0%
Reflux in deep cerebral veins > 0.5 s
61%
0%
IJV stenosis by B mode (Cross sectional area ≤ 0.3 cm2)
37%
0%
No Doppler flow in IJVs or VVs
52%
0%
Increase in IJV cross sectional area supine to sitting
55%
0%
Transcranial Doppler / Duplex Ultrasound Criteria
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Extra-cranial venous stenoses in all patients with 2 / 5 criteria
 Azygous – 86%
 Internal jugular – 91%
 Lumbar plexus atresia – 18%
No lesions in 48 controls undergoing venography
CCSVI & Multiple Sclerosis
Laupacis, CMAJ 2011
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Meta-analysis of U/S parameters (8 studies)
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MS patients
Healthy controls or patients with other neurologic diseases
Problems with the data
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Convenience sample (non-consecutive patients)
Inconsistent / poorly described blinding
Unexplained heterogeneity
Cerebrocervical Venous Congestion in MS
Doepp, Ann Neurol 2010
Patients
n = 56
Controls
n = 20
13/38 (38%)
6/30 (30%)
Reflux in the DCV
1
0
Proximal IJV stenosis (B mode)
0
0
Absent Doppler flow in both IJVs and or both VVs
5
1
Absent IJV lumen reduction with standing
4
3
One CCSVI criteria
10
4
Two CCSVI criteria
0
0
Criteria
Reflux > 0.88 sec in IJVs and/or VVs
Endovascular Treatment of CCSVI
Zamboni, J Vasc Surg 2009
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65 MS patients with CCSVI by TCD / Duplex U/S
PTA of IJV and azygous stenoses
 IJV – 53% patency at 18 months
 Azygous – 96% patency at 18 months
Neurologic improvement only in relapsing remitting MS
Pre-PTA
18 mo F/u
p
Relapse Free %
27%
50%
<.0014
MRI Gad + lesions %
50%
12%
<.0001
MSQOL, physical
66 ± 18
84 ± 16
.01
MSQOL, mental
61 ± 22
82 ± 13
.003
MS Functional Composite
5e-18 ± 0.7
0.65 ± 0.5
.008
CCSVI – The Critisisms
Khan, Ann Neurol 2010
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CCSVI does not adequately account for
 Autoimmune features of MS
 Genetic susceptibility (MHC and non-MHC linkage)
 Environmental factors
Geography
Strong association with Epstein-Barr infection
Low vitamin D levels
Primary demyelination not seen with other causes of
cerebral venous hypertension
 Central venous thrombosis
 Idiopathic intracranial hypertension
 Pulmonary hypertension
 COPD
Non-invasive findings not entirely reproducible
CCSVI & The Power of Social Networking
Chaffe et al, Nature 2011
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The evidence – 22 published papers
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The reality
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650, 000 Google results
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Educated, organized patient population
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Significant placebo effect in MS treatment
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Many interventionalists willing to offer procedure
“In today's era of 'Facebook equipoise', it may make sense
in rare cases to conduct a clinical trial before the desired
weight of scientific evidence accumulates; for instance, if
thousands of patients are exposing themselves to risks and
costs of unevaluated medical procedures”
CCSVI Clinical Trials

University of Ferrara, Ferrara, It (Paulo Zamboni, PI)
 500 multiple (RR & SP) patients randomized
Interventional treatment (angioplasty)
Sham interventional treatment
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Standard immunomodulatory treatment maintained
Endpoints
Objective neurologic scores
MRI
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Albany Medical College, Albany, NY (Manny Mehta, PI)
 2:1 randomization (600 patients)
Angioplasty
Sham interventional treatment

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Blinded assessment by participating neurologist
Endpoints
EDSS, MsQoL, Fatigue impairment scores
MRI
Chronic Cerobrospinal Venous Insufficiency
Current problems
 Lack of clinical equipoise among many neurologists
 Patient driven interventions (Will placebo be accepted?)
 Willing interventionalists outside of trials
 But, … this one eventually requires a multicenter RCT
 Vascular surgeons should own this investigation
 Initial description (Paulo Zamboni)
 Diagnostic technology (Vascular Lab)
 Limited durability of percutaneous approaches in young
patients may eventually drive an operative solution
 Will require close collaboration with neurological community
Although technological approaches to standard diseases have
evolved, this may be the first NEW vascular disease in our lifetimes
(and one that a smoking cessation and a statin won’t “cure”)
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